Comparative studies to understand the role of class II molecules expressed in epithelial cells. (360G-Wellcome-110106_Z_15_Z)

Molecules of the major histocompatibility complex (MHC) are crucial for many immune responses, presenting antigenic fragments (usually peptides) to T lymphocytes of the adaptive immune system, as well as being recognised by natural killer cells, myeloid cells and others as part of the innate immune system. Despite decades of research by many thousands of researchers, there is still much to understand about how the MHC works. Because of my interest in understanding the evolution of immunity, we have focused on the chicken MHC to elucidate the structure, function and evolution of immunity. Facilitated by the simple nature of the chicken MHC, this unique approach has determined fundamental principles underlying evolution of the adaptive immune system, underpinned advances in the poultry industry, and provided insights of importance to biomedical research. In our analysis of the chicken MHC class II system, we discovered differential expression: one class II B gene (BLB2) and a chaperon e/peptide editor gene (DMB2) being well-expressed in hemopoietic tissues, but another pair of genes (BLB1 and DMB1) being well-expressed in the intestine, specifically in intestinal epithelial cells (IECs). These intriguing results may indicate two parallel antigen presentation systems in chickens, one for the usual systemic immune system, and the other involving epithelial cells. Moreover, there are published data to suggest that a similar epithelial antigen presentation system might exist in m ice and humans. In order to understand the structural, functional and evolutionary basis of these phenomena, we will investigate the class II system in some detail, particularly to examine the possibility that there is a novel unifying concept for class II presentation in epithelial cells. We plan to: 1. Explore the tissue distribution of the chicken molecules fully (at RNA and protein levels), as a clue to mechanism and function. 2. Examine the mechanistic basis for the differential expr ession the chicken molecules, with particular attention to the huge distal promoter regions and the differences in 3UTR. 3. Determine the structural consequences of the differential expression by examining the peptides bound to the two chicken class II molecules in different tissues, and the effect of the two DMB molecules on the peptides presented. 4. Determine which cells and receptors recognize these class II molecules, and their functional importance in the immune response. 5. Explore the same issues in humans and mice, based on the existence of intact class II B genes with limited evidence for expression and function, as well as two DMB genes with differential tissue distributions in mice.